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Annual Regulatory GMP/GDP Inspection Survey2018 DataAuthor: TDEG Inspection team Date: 27/May/2019 Version: 2 public
Summary
2EFPIA ANNUAL INSPECTION SURVEY ‐ 2018 DATA
HistoryThe annual inspection survey was initiated in 2003 with the intent to gather data regarding inspections activities in the research‐based industry
IntentionMonitor trends and new focus areas of GMP/GDP inspections
Continue to promote reliance, collaboration and consistency in inspections by highlighting duplicate regulatory GMP/GDP inspections
Materialise the benefits of PIC/S membership in optimizing use of inspection resources with a harmonized risk‐based approach for inspections while maintaining patient safety
ScopeRegulatory GMP/GDP inspections & related ISO‐certifications for regulatory purpose
Manufacturing sites and affiliates
Inside and outside the Regulatory Authority’s own borders
Background and History
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The highest number of foreign inspections reported in the 2018 survey are
US, Russia followed by Japan, Turkey, Brazil, Mexico, Republic of Korea, EU, Belarus and Peru
Reportable trends from the survey compared with the previous year
Decrease
Foreign inspections by US (‐15%), Turkey (‐35%), Russia (‐40%), Brazil (‐45%), EU (‐51%)
Companies reported that Brazil, Canada, Israel and US waived inspections
Increase of
Foreign inspections by Australia, Chinese Taipei
The number of inspections requiring follow up; especially at affiliates (100% more)
Number of foreign inspections* indicated an increase
Based on data from 22 research‐based pharmaceutical companies
Survey Outcomes 2018
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* Foreign inspection: inspection conducted outside of the inspectorate’s own country/regionDomestic inspection: inspections conducted in the inspectorates own country/region
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The Ideal State is in Average One Biannual Inspection by the Local Inspectorate
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~ 1570 Inspections at ~ 760 Manufacturing sites
~ 1227 Inspections at ~ 730 Inspections at sites
n Inspections at 2n Manufacturing sites
How can we get there?
2017
2018
2025?
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Number of Foreign Inspections ordered by country (>1 inspections; EU as one entity)
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> 40Group 1
Only listed if more than 2 foreign inspections
> 15Group 2
*Inspectorate is a PIC/S member **PIC/S Applicant ***PIC/S Pre‐Applicant
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Number of Foreign Inspections by Country
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*Inspectorate is a PIC/S member **PIC/S Applicant ***PIC/S Pre‐Applicant
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Number of Foreign Inspections by Country
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Cut of 35‐36
*Inspectorate is a PIC/S member **PIC/S Applicant ***PIC/S Pre‐Applicant
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52%
PIC/S MEMBER inspectorates2017: 34%39% in 2018, when subtracting out the progress of applicants to member stage (Iran, Mexico, Turkey)
5%
PIC/S APPLICANT inspectorates2017: 20%The decrease is due to a higher number of inspectorates with an applicant status in 2017
18%
PIC/S PRE‐APPLICANT inspectorates2017: 17%
% of the reported foreign inspections are performed in countries, where the inspectorate is a PIC/S member
Survey Data Underline PIC/S is Facilitating Cooperation and Reliance
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Note: Applicants and Pre‐Applicants still need to demonstrate that they are equivalent and no GMP information is exchanged while they are in the accession / pre‐accession process.
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Opportunities: Efficient MRA Implementation Can Drive Reduction of Inspections
MRA US/EU
MRA
Inspections?
EU has decreased foreign inspections in US since 2014
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Not all provisions of the current MRA are implemented
Inspections called pre‐approval inspections (PAI) in the US – currently paused
Recognition of inspections of manufacturing sites in 3rd countries – pending
Biological products, if registered by CBER – no recognition by some offices in FDA
Medicinal Products in the EU with a Medical Device registered as ‘Combination Products’ in the US – different terminology leads to discrepancy in applicability
Unexpected consequences on EU GMP‐certificates
They are required for 3rd country registration and import
FDA (CDER only) may issues a product specific GMP statement under special circumstances – initiative started
Initiating efforts towards expanding the MRA to include
Waiving of import testing after inspection of manufacturing sites in a 3rd country
GMPs for Advanced Therapy Medicinal Products (ATMPs) / Cell and Gene Therapies (CGTs)
Challenges With Implementation
MRA US/EU
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Back to the baseline from previous years?
Evolution of Number of Foreign Inspections Versus Manufacturing Sites
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The survey showed that industry implemented the ICDRA recommendation
Industry is prepared to share inspection reports, usually redacted
Full information is shared upon request, where Intellectual Property is preserved
Assessment of WHO Recommendations Supporting the Ideal State
SHARE REPORTS FROM REGULATORY INSPECTIONS
NRA: National Regulatory AuthoritiesICDRA: International Conference of Drug Regulatory Authorities (by WHO)
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Industry support the ICDRA 2018 recommendations on risk based inspections and regulatory collaboration
Assessment of WHO Recommendations Supporting the Ideal State
SHARE REPORTS FROM REGULATORY INSPECTIONS
NRA: National Regulatory AuthoritiesICDRA: International Conference of Drug Regulatory Authorities (by WHO)
Adobe Acrobat Document
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An Approach Towards the Ideal State
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• Risk‐based inspection planning PIC/S guideline PI 037‐1, 1 January 2012 • GMP‐Inspection reliance, PIC/S guideline PI 048‐1, 1 June 2018• Classification of GMP Deficiencies, PIC/S guideline PI 040‐1, 1 January 2019
Trust
3. Reliance
4. Recognition*
2. Remote (desktop) review
1. On‐site inspection
Knowledge
5. Delegation*
*For inspections performed in s 3rd country, no legal barriers assumed
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Remote (desktop) review
Remote (desktop) review (PIC/S)PIC/S, GMP Inspection reliance, Guideline No PI 08‐1, 01. June 2018
Confirming GMP compliance through remote (desktop) inspection, where appropriate, without undertaking an onsite inspection
Remote (Desktop) Review ‐ Paper‐based Inspections
TERMINOLOGY
Information from other inspectorates
Information provided by a
company
Information gathered from other sources
‘Paper‐base inspection’
Paper based inspections11/22 companies reported in the survey
Providing documents to an inspectorate, without an on‐site inspection
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Companies could submit standardised documentation package
May include, and may be limited to SMF, APQR for product in scope, valid GxP certificates and/or WHO CPP, manufacturer’s licence, list of inspections / inspections reports (e.g. EIR‐US only) and companies responses.
All other documents would be available to be reviewed on site by the localinspectorate
Talking Points to Optimise the Use of Opportunities in the Inspection Process
REMOTE (DESKTOP) REVIEW ‐ PAPER‐BASED INSPECTIONS
* Remote (desktop) review: PIC/S, GMP Inspection reliance, Guideline No PI 08‐1, 01. June 2018
Companies suggest a remote (desktop) review according to PIC/S* as an alternative to a requested for an on‐site foreign inspection
Remote (desktop) review according to PIC/S* should be considered as alternative to a foreign inspection
A
B
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Promoting common understanding of expectations with a simplified administrative process related to inspections
Utilizing synergies between inspectorates and fostering cooperation and reliance including MRAs
Focusing resources on domestic inspections and minimize inspections in 3rd countries
Optimise the Effectiveness of Inspectional Oversight of GMP/GDP Operations
STRATEGIC INTENTION ON INSPECTIONS
Method
System
Priority
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Basing regulations, rules and practices on science principles and incorporating risk‐based approaches
Sharing knowledge and looking for opportunities in the existing legal framework rather than creating ‘new’ fragmented GMP/GDP guidelines in the EU
Assessing new products and technologies in the context of the existing understanding of GMP requirements and oversight
Alignment on documentation requirements prior to an on‐site inspection and/or for a paper‐based inspection as part of remote (desktop) review
Inspection Method
OTHER REFLECTIONS ON CONTINUOUS IMPROVEMENT
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Sharing good practice and aligning on a common interpretation of GMP/GDPs
Classification system for observations (PIC/S*)
Encouraging trust and dialogue among inspectors
Maximise effectiveness of existing harmonisation forums e.g., PIC/S, ICMRA, ICH, WHO, APEC
Facilitate education
Fostering reliance and recognition towards delegationMaturity level of authorities (e.g., PIC/S, WHO, MRA US/EU)
Leverage the benefit from reliance on inspection outcomes
Inspection System
OTHER REFLECTIONS ON CONTINUOUS IMPROVEMENT
*Classification of GMP Deficiencies, PIC/S guideline PI 040‐1, 1 January 2019
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Fully deploying the US/EU MRA to maximise benefits
Harmonized documentation package for desk assessments and/or inspection preparation
Sharing results of inspection outcomes among regulators and by industry
Promoting reliance of outcomes from domestic inspections
Inspection Priority
OTHER REFLECTIONS ON CONTINUOUS IMPROVEMENT
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For Industry and Regulators
Globally aligned GMP/GDPs principles
Facilitate access to innovation
Resource‐efficient inspection processes
For Patients
Assurance of Quality and optimised regulatory oversight
Accelerate Time to Market
Get access to new and innovative medicines
Expected Benefits
OTHER REFLECTIONS ON CONTINUOUS IMPROVEMENT
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Guidance for inspectorsPIC/S, A recommended model for risk‐based inspection planning in the GMP environment Guideline, Guideline PI 037‐1, 01. Jan 2012
PIC/S, GMP Inspection reliance, Guideline No PI 048‐1, 01. June 2018
PIC/S, Classification of GMP Deficiencies, Guideline No PI 040‐1, 01. January 2019
Scientific PapersA. Meshkovskij, S. Rönninger, National GMP Inspection Practice for Biotech Pharmaceuticals: Commonalities, Differences, Opportunities, CIS GMP News, 2018, 1, 26‐31. https://gmpnews.net/magazine/gmpnews‐eng‐2‐1‐2018/#page/26
H. Jin, N. Carr, H. Rothenfluh, TGA, Medicines Regulations: Regulating Medicines manufacturers: Is an onsite inspection the only option?, WHO Drug Information, 31/2, 2017, 153‐157.
EMA, WHO, TGA, US‐FDA, EDQM,Council or Europe, ANSM, DMA, HPRA AIFA, MHRA, Report on the International Active Pharmaceutical Ingredient Inspection Programme 2011 – 2016, March 2018, 1‐13.
S. Rönninger, J. Berberich, V. Davoust, P. Kitz, A. Pfenninger, Landscape of GMP/GDP inspections in research‐based pharmaceutical industry, Part I: Data, Pharm. Tech. Europe, January, 2017, 6‐10.http://www.pharmtech.com/gmpgdp‐inspection‐landscape‐part‐i‐data ; Part II: Considerations and Opportunities, Pharm. Tech. Europe, February, 2017, 5‐9. http://www.pharmtech.com/gmpgdp‐inspections‐landscape‐part‐ii‐considerations‐and‐opportunities
A. Meshkovskij, S. Rönninger, GMP Inspection practice: a case for global benchmarking, convergence and mutual reliance/recognition, The GMP News, 2017, 2‐9 (Rus).
EFPIA Annual Inspection Survey, results 2017 https://www.efpia.eu/media/361849/_efpia‐2017‐reg‐inspection‐survey_public‐summary.pdf
Industry Position PapersEFPIA: Enhanced Good Manufacturing and Good Distribution Practices (GMP/GDP) Inspection Efficiency, 19. May 2014.
EFPIA / PhRMA: A Concept for Harmonized Reporting of Inspections, 29. May 2015; addendum of the PhRMA White Paper: ‘Mutual Recognition of Drug GMP Inspections by U.S. & European Regulators’, 15. May 2015.http://www.efpia.eu/uploads/EFPIA_Position_Paper_A_Concept_for_Harmonized_Reporting_of_Inspections_final.pdf
IFPMA: Convergence of Good Manufacturing Practice (GMP) standards and Related Inspections, 9. June 2017 https://www.ifpma.org/wp‐content/uploads/2017/06/IFPMA‐Position‐on‐GMP‐Convergence‐Final‐_9June2017.pdf
IFPMA Infographic: https://www.ifpma.org/wp‐content/uploads/2018/02/GMP_IFPMA_02‐20‐2018‐WEB.pdf
Additional References
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• Johnson & Johnson
• Merck
• Merck Sharp & Dohme
• Novartis
• NovoNordisk
• Pfizer
• Roche
• Sanofi (incl. Sanofi Pasteur)
• Servier
• Teva
• UCB
Almirall
Amgen
AstraZeneca
Bayer
Boehringer Ingelheim
Biogen
Bristol‐Myers Squibb
Chiesi
Eli Lilly and Company
Grünenthal GmbH
GlaxoSmithKline
Contributors to the EFPIA Inspections Survey 2018
ACKNOWLEDGEMENT
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EFPIA Brussels OfficeLeopold Plaza Building * Rue du Trône 108
B‐1050 Brussels * BelgiumTel: + 32 (0)2 626 25 55
www.efpia.eu * [email protected]